It is reported that venlafaxine of formula (II), 1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol, is an inhibitor of 5-hydroxytryptamine (5-HT) and norepinephrine (NA) reuptake, and is widely used for treatment of depression disorders, etc. Furthermore, after the compound of formula (II) is uptaken, it is metabolized in liver to form a strongly active metabolite (III), 1-[2-dimethylamino-1-(4-hydroxyphenyl)-ethyl]-cyclohexanol and weakly active metabolites, (IV), 1-[2-methylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol, and (V), 1-[2-methylamino-1-(4-hydroxyphenyl)-ethyl]-cyclohexanol, wherein the compounds (II) and (III) have the same therapeutic effects (see also, U.S. Pat. No. 4,535,186, US20040176468, US20040147601, US20030191347, Wyeth Effexor description).
As compared to the uptake of the compound (II), the direct uptake of the compound (III) for treating diseases related to central nerve system, especially depression, has the advantage of the principle of using a single active compound, facilitates the adjustment of dosage and therapeutic effects, alleviates side-effects, and reduces the risk of interaction with other drugs (see U.S. Pat. No. 6,673,838). However, the compound (III) with more hydroxyl groups results in the increase of hydrophilicity, and therefore decreases absorption rate via oral or transdermal and leads to possibly more pre-system side-effects due to unabsorbed drug. For overcoming the above drawbacks of the compound (III), a series of derivatives [compounds of formula (I)] of compound (III) are synthesized, and these compounds as the prodrugs of the compound (III) are metabolized in vivo to produce the compound (III), thereby exhibiting therapeutic effects.
